The present invention relates to a novel orally administrable pharmaceutical preparation containing an active ingredient to be released in the lower part of the gastrointestinal tract, i.e. in the large intestine and especially in the colon.
There is an important and increasing need of a pharmaceutical delivery system which enables a selective release in the lower part of the gastrointestinal tract, i.e. in the large intestine and especially in the colon.
Such a delivery system would be of great benefit in the case of a therapy which requires the administration of a medicament in the large intestine. A first therapeutic application of such a system is for the treatment of colonic and rectal disorders. Orally administrable pharmaceutical preparations are frequently found to be ineffective in this respect as a result of the absorption or degradation of the pharmacologically active ingredient in the digestive tract before the colon or rectum is reached. Consequently, the delivery of pharmacologically active agents to the colon or rectum has conventionally been achieved by rectal administration, by the use of either suppositories or enemas. However, the spreading of these preparations within the large intestine is highly variable even in healthy subjects (Int. J. Pharm. 25, 191-197, 1985) and it often fails to reach the trasverse and ascending colon. In particularly, suppositories are only effective for the rectum and the sigmoid whereas enemas rarely reach the ascending colon. Furthermore, rectal administration generally is less convenient and less acceptable than oral administration. As a consequence, it is evident that orally administrable preparations with a colon selective release would be very effective and convenient for the treatment of large intestine and of rectal disorders.
Colon-localized release of the active ingredients is also desiderable in the treatment of infectious diseases of large intestine caused by microbial growth of pathogenic agents. In such a case, by using an orally administrable colon selective delivery system, a high in-situ concentration level of antibacterial agents can be attained and a more beneficial local effect with respect to common preparations can be ensured.
The need of a colon selective delivery system is also highly desirable for the administration of antitumour agents in the cancer therapy of large intestine. In fact, the release of antitumour agents specifically in this part of the gastrointestinal tract which is affected by the disease allows to reach locally an high effective drug concentration and, at the same time, to strongly reduce the side effects due to absorption in the small intestine.
An other therapeutic possibility of a colon selective delivery system is to administer drugs which are poorly absorbed in the small intestinal tract and to give significant therapeutic effect either locally or systemically when they reach the large intestine.
For instance in the treatment of irritable bowel syndrome some antispasmodic agents show a direct action on the smooth muscle. Therefore, by using a colon selective delivery system, such antispasmodic agents can produce their effects in their specific site of action avoiding any (even erratic) small intestinal absorption and obtaining a more selective effect on the large intestinal smooth muscle.
An other very important reason for the application of the colon selective delivery system is the possibility to administer orally drugs which are degraded by the gastroduodenal juices or which induce side effects in the stomach or small intestine.
Particularly, a colon selective delivery system can be successfully applied for the oral administration of proteins and peptides, of which the poor efficacy if orally administered, is well known owing to their degradation in gastric and duodenal juices.
It is also known that Peyer's patches which are present in the ileocecal junction can have a role in protein absorption through lymphatic uptake. As a consequence, the release of proteins and peptides in the lower part of the intestine can be a means to permit an oral administration of such compounds which for the above difficulties are normally administered through parenteral route. It is evident the great advantage resulting from this possibility is much more acceptable and convenient for patients than injection formulations.
In the last years many attempts have been made to obtain an oral pharmaceutical preparation which enables drugs to be released in the lower region of the intestine preferentially in the large intestine or colon.
From EP 40590 orally administrable pharmaceutical preparations consisting of coated granules whose coating comprises a mixture of an anionic carboxyacrylic polymer which is soluble only at pH 5.5 and a water insoluble polymer selected from quaternary ammonium substituted acrylic polymers are known. The disadvantage of this delivery system is that this release can occur even after only 1-2 hours at pH 7 because of the presence of a mixture of the two polymers, for which there is the possibility that part of the drug is released before reaching the colon. From WO 83/00435 a solid oral dosage form coated with a suitable amount of an anionic polymer (Eudragit.RTM.S) soluble in aqueous medium only at pH 7 is known. The disadvantage of this formulation is due to the use of significant amount of Eudragit.RTM.S so that the dosage form remains intact until it reaches the colon. In such a case there is the possibility that the preparation is eliminated before a complete dissolution of the coating takes place.
From EP 225189 a colon selective delivery system which consists of a soft gelatin capsule containing the drug (proteins and peptides) and coated with a film forming composition which is insoluble at pH below 7 is known. The coating composition consists of a mixture of suitable amounts of copolymer of methacrylic acid and of its ester (Eudragit.RTM.S, L, S). Due to biological variability of pH in the gastro-intestinal tract, the reliability of this system is rather low and the relevant risks are the release before the colon due to an early pH above 7 or the elimination of the intact form without release in the colon.
From BE Pat. 903502 an osmotic system to release the drug in the colon is also known. In this case the release is based on the use of enteric coating polymers which dissolve in the intestine and prime the osmotic pump.
BE-A-652807 relates to an orally administrable preparation for gradual and sustained release in the colon consisting of:
(a) a core containing a therapeutically active susbtance PA0 1) an inner layer, comprising a suitable amount of an anionic copolymer which is soluble at pH above 7.0 and a suitable plasticizer; PA0 2) an intermediate layer, comprising a suitable amount of a gelling polymer which swells in the enteric juice at any pH building up a thick gel layer; PA0 3) an outer layer, comprising a suitable amount of a gastro-resistent polymer able to dissolve quikly in the intestine.
(b) 1. an inner layer soluble at acidic pH and insoluble at basic pH PA1 2. an intermediate layer water soluble at any pH (consisting or arabic gum, gelatin, page 11-12 Ex. in particular page 12, line 12) PA1 3. an outer layer soluble at basic pH and insoluble at acidic pH.